Toshikazu Hashimoto

Neonatal exposure to sevoflurane causes significant suppression of hippocampal long-term potentiation in postgrowth rats.

BACKGROUND: The inhaled anesthetic sevoflurane is commonly used for neonates in the clinical setting. Recent studies have indicated that exposure of neonatal rodents to sevoflurane causes acute widespread neurodegeneration and long-lasting neurocognitive dysfunction. Although acute toxic effects of sevoflurane on cellular viability in the hippocampus have been reported in some studies, little is known about the effects of neonatal sevoflurane exposure on long-term hippocampal synaptic plasticity, which has been implicated in the processes of learning and memory formation. Our study is the first to examine the long-term electrophysiological impact of neonatal exposure to a clinically relevant concentration of sevoflurane. METHODS: On postnatal day 7, rats were exposed to sevoflurane (1% or 2% for 2 hours) with oxygen. To eliminate the influence of blood gas abnormalities caused by sevoflurane-induced respiratory suppression, a group of rats were exposed to a high concentration of carbon dioxide (8% for 2 hours) to duplicate respiratory disturbances caused by 2% sevoflurane exposure. RESULTS: Exposure of neonatal rats to 2% sevoflurane for 2 hours caused significant suppression of long-term potentiation (LTP) induction in the postgrowth period. There was no significant difference between the control group and the CO2-exposed group in LTP induction, indicating that sevoflurane-induced LTP suppression was not caused by blood gas abnormalities. CONCLUSION: Our present findings indicate that neonatal exposure to sevoflurane at a higher concentration can cause alterations in the hippocampal synaptic plasticity that persists into adulthood.

Neonatal administration with dexmedetomidine does not impair the rat hippocampal synaptic plasticity later in adulthood

Background and objective:  The use of dexmedetomidine (DEX), a selective alpha‐2 agonist, in pediatric practice is expanding as a result of its desirable properties. To clarify the long‐term neurological consequences of neonatal administration of DEX, we investigated the long‐term effects of neonatal administration of DEX on hippocampal synaptic activity.

Neonatal exposure to high concentration of carbon dioxide produces persistent learning deficits with impaired hippocampal synaptic plasticity

Although respiratory complications with blood gas abnormalities contribute significantly to neurodevelopment in the immature brain, little is known about the mechanisms via which blood gas abnormalities, such as hypoxic hypercapnia, impair neurocognitive outcomes. To investigate the possible long-term consequences of neonatal exposure to hypoxic hypercapnia regarding learning ability, we investigated the effect of neonatal hypoxic hypercapnia on later functions in the hippocampus, which is a structure that has been implicated in many learning and memory processes. Neonatal rat pups (postnatal day 7; P7) were exposed to a high concentration of carbon dioxide (CO2; 13%) for 2 or 4h. Exposure to CO2 in P7 rat pups caused blood gas abnormalities, including hypercapnia, hypoxia, and acidosis, and disrupted later learning acquisition, as assessed in 10-week-old adult rats subjected to a Morris water maze test. Induction of long-term potentiation (LTP) in the synapses of the hippocampal CA1 area was also impaired, whereas the paired-pulse responses of population spikes exhibited a significant increase, in CO2-exposed rats, suggesting decreased recurrent inhibition in the hippocampus. Such long-lasting modifications in hippocampal synaptic plasticity may contribute to the learning impairments associated with perinatal hypoxic hypercapnia and acidosis.

Isoflurane bidirectionally modulates the paired-pulse responses in the rat hippocampal CA1 field in vivo.

BACKGROUND:We studied the effects of isoflurane on hippocampal synaptic transmission and paired-pulse plasticity, under in vivo intact interneuron circuitry. METHODS:Using rats chronically implanted with electrodes, excitatory postsynaptic potential (EPSP) and population spike amplitude (PSA) were measured in the hippocampal CA1 field by stimulating Schaffer collaterals. The lungs of the rats were mechanically ventilated with 0.25–1.5 minimum alveolar anesthetic concentration (MAC) isoflurane. A control value was obtained in the absence of isoflurane. RESULTS:Isoflurane depressed EPSP responses and enhanced synaptic efficacy. PSA was not depressed except under high concentrations, presumably reflecting a well-balanced combination with the decreased EPSP and enhanced synaptic efficacy. Low concentrations of isoflurane (0.25 and 0.5 MAC) increased paired-pulse facilitation (PPF), whereas a high concentration of isoflurane (1.5 MAC) prolonged the paired-pulse depression. CONCLUSIONS:Isoflurane appeared to affect multiple sites of CA1 synapses: 1) the depression of presynaptic glutamatergic transmission as shown by depressed EPSP and increased PPF; 2) the depression of pyramidal neurons as shown by prolonged PPF and depressed PSA under high concentration; and 3) the depression of interneurons as shown by the greater synaptic efficacy. The degree of each of these inhibitory effects seemed to vary at different concentrations, and the overall direction of the synaptic properties may depend on the balances between these inhibitory effects in vivo.

Altered synaptic transmission in rat anterior cingulate cortex following peripheral nerve injury.

BACKGROUND Patients with neuropathic pain present not only with persistent pain but also a complex set of additional symptoms, including mood disorders and cognitive disturbance. Given the important roles of the anterior thalamic nuclei (ATN) and anterior cingulate cortex (ACC) in the cognitive and emotional aspects of pain, investigation of the properties of ATN-ACC synapses will help us to understand the mechanisms underlying neuropathic pain. METHODS We studied changes in ATN-evoked ACC excitatory postsynaptic potentials (EPSPs) induced by neuropathic pain in a rat model under halothane anaesthesia. RESULTS Neuropathic pain caused significant suppression of EPSPs in the ACC compared with rats subjected to sham surgery. Similar to previous evidence, acute inflammatory pain induced by formalin injection into the hind paw significantly increased synaptic efficacy in the ACC compared with naive rats. Neither of the pain paradigms altered the paired-pulse responses. CONCLUSIONS A possible explanation for the neuropathic pain-related suppression of EPSPs is that the ACC was already sufficiently active at baseline as a result of neuropathic pain, and ATN stimulation could not further increase the already elevated level of ACC activity. This abnormal excitability of the ATN-ACC synapse may be important in understanding the mechanism underlying neuropathic pain, particularly with respect to the affective and cognitive aspects.

Anatomical features of the right internal jugular vein in infants and young children undergoing heart surgery for congenital disease: comparison between cyanotic and noncyanotic patients

PurposeIt has been reported that children with cyanotic heart disease have elevated systemic levels of vascular endothelial growth factor, which may be related to the development of vessels. However, it is unknown whether the anatomical features of the internal jugular vein (IJV) differ between cyanotic and noncyanotic children. In this study, we compared anatomical information about the IJV of these two groups of patients.MethodsWe measured the distance between the right IJV and the right carotid artery (distance), the diameter of the IJV (diameter), and the depth of the IJV from the skin (depth), using an ultrasound device, in 100 children (0–34 months) undergoing heart surgery for congenital disease. First, we evaluated the relationship of these measurement values with patient demographic data (age, height, and body weight). Next, we evaluated the effect of the 15° Trendelenburg position on these measurement values.ResultsThere were 62 cyanotic and 38 noncyanotic patients. Distance and diameter, but not depth, were well correlated with the demographic data in both patient groups. Diameter in cyanotic patients was highly correlated with the demographic data. Clinically significant changes in the measurement values were not observed in the 15° Trendelenburg position compared with the horizontal position in either patient group.ConclusionThe anatomical features of the right IJV in infants and young children with congenital heart disease were not different in cyanotic and noncyanotic patients, except for the relationship between diameter and the demographic data. In the small patients examined in our study (72% of them were infants), the diameter of the IJV was not sufficiently enlarged by the Trendelenburg position, regardless of whether the patients were cyanotic or noncyanotic.

Plantar injection of formalin in rats reduces the expression of a potassium chroride cotransporter KCC2 in the spinal cord and a kinase inhibitor suppresses this reduction

Brain-derived neurotrophic factor (BDNF) is released from activated microglia during neuropathic pain and is hypothesized to downregulate the expression of the potassium chloride cotransporter 2 (KCC2) via the TrkB receptor. Previous studies reported that KCC2 is downregulated 5 min after the plantar injection of formalin in rats; however, the mechanism behind this decrease in KCC2 expression during acute inflammatory pain remains unknown. In this study, we determined whether the TrkB receptor contributes to the expression of KCC2 during the acute pain. Five minutes after the plantar injection of formalin in rats, the ratio of KCC2-immunoreactive area in layer II of the spinal cord significantly decreased on the stimulated side compared to the unaffected side. On the other hand, this response was inhibited by the injection of a kinase inhibitor, K252a, in the subarachnoid space 15 min before the formalin injection. These findings suggest that in acute pain, the TrkB receptor may contribute to the decrease in the expression of KCC2.

Neurotoxicity of Anesthetic Agents for Developing and Adult Brain

1. Neurotoxicity of anesthetic agents to the developing brain The neurotoxicity of various anesthetic and sedative agents to the developing brain has been clearly established in various laboratory animals, including subhuman primates. According to recent reports, anesthetic agents which block N-methyl-D-aspartate-type glutamate receptors and/or activate gammaaminobutyric acid-A receptors have neurotoxic properties when used during synaptogenesis. Despite numerous reports, however, the precise mechanisms underlying this neurotoxicity remain unknown. Moreover, it is believed that these results cannot be easily extrapolated into human clinical practice. The results of clinical studies on the neurotoxicity of anesthesia in pediatric patients have been conflicting, and definitive epidemiological evidence remains to be established. Therefore, it would be inappropriate to suggest that anesthesiologists change their anesthetic practice based on these studies at the present time. 2. Neurotoxicity of anesthetic agents to the adult brain Postoperative delirium (POD) and postoperative cognitive dysfunction (POCD) are cognitive complications occurring after surgery under anesthesia. POD is a transient disturbance of consciousness, attention, cognition, or perception or disorganized thinking and can lead to various complications. It is important to determine the preoperative and intraoperative risk factors for POD in tackling this problem. It is also crucial to recognize and manage its underlying causes in ensuring an appropriate environment for a POD-free recovery. POCD is usually defined as persistent cognitive deterioration, which is clinically diagnosed using various types of neuropsychological tests. POCD and POD are both associated with the aggravation of complications after surgery under anesthesia. Although various factors such as systemic neuroinflammation have been postulated as causes of POCD, its underlying pathogenic mechanism remains to be clearly elucidated. POCD is often observed following cardiac surgery. However, recent studies have revealed that it can occur regardless of type of surgery or anesthesia. Suggested risk R. Kato, M.D., Ph.D. (*) • T. Hashimoto, M.D., Ph.D. • Y. Morimoto, M.D., Ph.D. Department of Anesthesiology and Critical Care Medicine, Hokkaido University Graduate School of Medicine, North 15, West 7, Kita-ku, Sapporo 060-8638, Japan e-mail: katorui@med.hokudai.ac.jp

Gastric intramucosal perfusion during descending aortic repair under femoro-femoral bypass.

The changes in gastric mucosal perfusion during distal aortic perfusion with femoro-femoral bypass (F-F bypass) were assessed by air-automated gastric tonometry. A prospective study was performed in six patients who underwent descending aortic surgery for aortic aneurysm under F-F bypass with mild hypothermia (34°C). Gastric intramucosal pH (pHi) and PaCO2-PgCO2 gap (PCO2 gap) were measured. Data are presented as means and standard deviations and analyzed by using one-way analysis of variance followed by Scheffe test. Perioperative variables of hepatorenal functions are also evaluated. The PCO2 gap significantly increased during F-F bypass (3.0 ± 2.1 mm Hg at control, 14.2 ± 5.5 mm Hg during F-F bypass; p = 0.004), indicating abnormal gastric mucosal perfusion during F-F bypass. Significantly low pHi was found at weaning from F-F bypass (7.35 ± 0.05 at control, 7.21 ± 0.10 at weaning; p = 0.009), which might be related to progressing systemic metabolic acidosis. No impairment of hepatorenal functions was observed after the surgery. Distal perfusion with F-F bypass during descending aortic surgery could impair the gastric mucosal perfusion, but may have little effect on postoperative visceral dysfunction.